Preparation of bile acids and intermediates thereof

1. A method for preparing deoxycholic acid or a salt thereof which method comprises:

a) hydrogenation of a compound of formula 129:

with hydrogen so as to provide compound of formula 130:

where P is a hydroxyl protecting group and R is C 1 -C 6 alkyl;

b) contacting compound 130 with lithium aluminum tri-t-butoxy hydride to provide compound 131:

and

c) deprotection and hydrolysis of compound 131 to provide for deoxycholic acid or a salt thereof.

2. The method of claim 1 , wherein P is acetyl and R is methyl.

3. A method for preparing deoxycholic acid or a salt thereof which method comprises:

a) hydrogenation of a compound of formula 129a:

wherein Ac is acetyl, with hydrogen in the presence of 10% palladium on carbon and ethyl acetate to provide compound of formula 130a:

b) contacting compound 130a with lithium aluminum tri-t-butoxy hydride in the presence of tetrahydrofuran to provide compound 131a:

and

c) deacetylation and hydrolysis of compound 131a in the presence of sodium hydroxide and a mixture of tetrahydrofuran and methanol to provide for deoxycholic acid or a salt thereof.

4. The method of claim 3 which further comprises crystallization of deoxycholic acid or a salt thereof as produced in part c).

5. A method for preparing a compound of formula 1.1:

comprising hydrogenation of a compound of formula 1.0:

with H 2 in the presence of a Pd/C catalyst and DMF.

6. The method of claim 5 , wherein the Pd/C catalyst is 10% Pd/C.

7. The method of claim 6 , wherein the compound of formula 1.1 is more than 99% pure.

8. A method for preparing deoxycholic acid (DCA) or a pharmaceutically acceptable salt thereof:

said method comprising

(a) hydrogenation of 9 α-hydroxyandrost-4-en-3,17-dione 1.0 with H 2 in the presence of a Pd/C catalyst to form compound 1.1

(b) reacting compound 1.1 with H 2 SO 4 to form compound 1.2

(c) reacting compound 1.2 with LiA 1 (OtBu) 3 H to form compound 1.3 or a mixture of 1.3 and 1.4

(d) reacting compound 1.3 with Ph 3 PCH 2 CH 3 + Br to form compound 1.5

(e) converting compound 1.5 to a compound of formula 1.6

(f) reacting the compound of formula 1.6 with methylpropiolate of the formula CH≡CC(O)OCH 3 or methyl acrylate of the formula CH 2 ═CHC(O)OCH 3 , in the presence of EtAlCl 2 to form a compound of formula 1.7 wherein, and the dashed line is a single or double bond;

(g) hydrogenation of the compound of formula 1.7 with H 2 to form a compound of formula 1.8

(h) oxidation of the compound of formula 1.8 to form a compound of formula 1.9

(i) hydrogenation of the compound of formula 1.9 with H 2 in the presence of a Pd/C catalyst to form a compound of formula 2.0

(j) reacting the compound of formula 2.0 with LiAl(OtBu) 3 H to form a compound of formula 2.1

and

(k) deacetylation and hydrolysis of the compound of formula 2.1 to form deoxycholic acid or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 which further comprises crystallization of deoxycholic acid or a salt thereof as produced in part (k).

10. The method of claim 8 , wherein the Pd/C catalyst in step (a) is 10% Pd/C.

11. The method of claim 8 , wherein the hydrogenation is carried out in DMF.